The majority of fatalities in intensive care units are related to dysregulation of the immune system. Acute illnesses, such as trauma, pancreatitis, ischemia and severe infections, evoke an intense local inflammatory response at the site of injury or infection that subsequently promotes a systemic inflammation response and in many cases, death. Recent investigations have shown that tissue damage (i.e., cell death) liberates proteins that can induce systemic inflammation. Namely, HMGB-1, a nuclear DNA binding protein, is released from damaged cells, promoting, in turn, the release of pro-inflammatory cytokines from monocytes via receptors for advanced glycation end products (RAGE) and Toll-like receptors (TLR). Preliminary data from our laboratories shows for the first time that mitochondrial proteins induce the activation of monocytes. as reflected by pro-inflammatory cytokine production. Interestingly, mitochondrial transcription factor A (mtTFA) is abundant in mitochondria, and is functionally and structurally similar to HMGB-1. Thus, we hypothesize that mitochondrial proteins, particularly mtTFA, may activate monocytes via RAGE receptor recognition and are capable of promoting a systemic inflammation response The following aims are proposed: SPECIFIC AIM 1: To identify mitochondrial proteins which induce the release of cytokines from monocytes in vitro. SPECIFIC AIM 2: To determine if mitochondrial proteins induce a systemic inflammatory response in mice. SPECIFIC AIM 3: To determine if mitochondrial proteins, particularly mtTFA, activate human peripheral blood monocytes via receptors for advanced glycation end products (RAGE) and/or Toll-like receptors -2 and -4. These investigations have important implications toward better understanding the feed-forward mechanisms through which initial tissue injury begets systemic inflammation, culminating in organ failure and death. Once the mitochondrial proteins responsible for the promotion of monocyte/macrophage activation, and the mechanism of monocyte activation has been identified, new therapeutic targets may be identified to attenuate unregulated systemic inflammation in critically ill patients. [unreadable] [unreadable] [unreadable]